Just out of sight: determining gene regulatory loci to improve coloboma diagnoses

Brief Lay Background

During pregnancy, the development of the eye involves the closure of an ‘optic fissure’ at around 6 weeks gestation. Disruption to this process can result in a condition called coloboma, where the lower-most parts of the light-sensitive layer of the eye (the retina) fail to develop properly and may affect vision. Instead of fusing together, there is a gap which can extend from the coloured part of the eye at the front (the iris) through to the specialised cable that sends visual signals from eye to brain (the optic nerve) at the back.

What problem/knowledge gap does it help address?

Despite evidence suggesting a genetic explanation, most people with coloboma do not know what has caused the condition. Current efforts to find causative gene faults often look directly within genes (the DNA coding instructions), but there are also non-coding areas involved in eye development within the genome (the complete set of DNA).

Further exploration of the genome and its non-coding regions is warranted as 70% of people with coloboma that have had their DNA sequenced do not have a genetic diagnosis.

Aim of the research project

To identify the important regions of DNA that regulate the genes involved in optic fissure closure and compare these regions in people with coloboma.

Key procedures/objectives

1. Use a chick model of the eye to examine the optic fissure tissue and identify non-coding regions that regulate the closure process.
2. Compare these regions across different developmental stages and cell types to identify key regulatory networks (known as 'eRegulons').
3. Map significant eRegulons to the human genome and search for coloboma-related genetic variants using existing patient data.
4. Use available data from families to compare variants and determine their inheritance.
5. Disseminate the findings across the scientific community and public/patient outreach groups.

Potential impact on people with sight loss

Identifying the genetic causes has immediate impact for patients and families to understand why they have been affected with coloboma. Longer-term, identifying the gene regulatory networks, candidate genetic loci and active transcription factors will help piece together the genetic basis of optic fissure closure in terms of both the genes involved, and how these are regulated during important developmental processes in the embryonic eye.

This knowledge of eye development will support further work to understand gene-environment interactions to explore preventative measures and identify risk-factors for coloboma.